Crosstalk between the plasma membrane and cell-cell adhesion maintains epithelial identity for correct polarised cell divisions

Polarised epithelial cell divisions represent a fundamental mechanism for tissue maintenance and morphogenesis; their dysregulation often leads to developmental disorders and cancer. Morphological and mechanical changes in the plasma membrane influence the organisation and crosstalk of microtubules and actin at the cell cortex, thereby regulating the mitotic spindle machinery and chromosome segregation. Yet, the precise mechanisms linking plasma membrane remodelling to cell polarity and cortical cytoskeleton dynamics to ensure accurate execution of mitosis in mammalian epithelial cells remain poorly understood. Here we experimentally manipulated the density of mammary epithelial cells in culture, which led to several mitotic defects. We found that perturbation of cell-cell adhesion integrity impairs the dynamics of the plasma membrane during mitosis, affecting the shape and size of mitotic cells and resulting in defects in mitosis progression and generating daughter cells with aberrant cytoarchitecture. In these conditions, F-actin-astral microtubule crosstalk is impaired leading to mitotic spindle misassembly and misorientation, which in turn contributes to chromosome mis-segregation. Mechanistically, we identify the S100 Ca2+-binding protein A11 (S100A11) as a key membrane-associated regulator that forms a complex with E-cadherin and LGN to coordinate plasma membrane remodelling with E-cadherin-mediated cell adhesion and LGN-dependent mitotic spindle machinery. We conclude that plasma membrane-mediated maintenance of mammalian epithelial cell identity is crucial for correct execution of polarised cell divisions, genome maintenance and safeguarding tissue integrity.